In the United States, approximately 160 billion gallons of solvents are used each year. Many of these solvents are volatile and are listed in the United States' Clean Air Act as substances to be avoided. The majority of solvents further contribute to depletion of the ozone layer (especially evident with chlorofluourocarbons), are highly toxic (especially chlorinated solvents), are a chief factor in birth defects, and, in addition, are a major cause of fires and explosions.
Over the past few years, significant research has been directed toward the development of new technologies for environmentally benign processes (green chemistry), which are both economically and technologically feasible. An important area of green chemistry deals with solvent minimization.
Solvent minimization processes are those conducted in minimal amount of solvent or are conducted in solvent-free environments. Solvent-free processes always exhibit the greatest efficiency because they eliminate the costs of processing, handling and disposal of the solvent. Limited success has been achieved with solvent minimization processes employing aqueous systems, ionic liquids, immobilized solvents, dendrimers, amphiphilic star polymers or supercritical fluids. The major challenge encountered in solvent minimization processes is the lack of a common phase (typically provided by the solvent medium) which brings the reactants into closer proximity.
Solvent minimization processes are especially desired in the manufacture of certain compounds used as active ingredients in pharmaceuticals. Exemplary of the solvent processes to synthesize N-acetyl-p-aminophenol (APAP or acetaminophen, sold under the trademark Tylenol®) are the Mallinckrodt Process, Celanese Process, Sterling Process and Monsanto Process. Such processes, named after the formulator practicing the process, are summarized below: These processes are the subject of numerous patents.
For example, in the Monsanto Process, described in U.S. Pat. Nos. 3,334,587 and 3,076,030, both of which are herein incorporated herein by reference, as well as the Sterling Process, p-nitrophenol is reduced to p-aminophenol which is then acetylated to render N-acetyl-p-aminophenol. The reduction of p-nitrophenol to produce p-aminophenol involves hydrogenating the p-nitrophenol in the presence of a catalyst such as platinum, palladium, nickel, a noble metal, or an oxide of platinum, palladium, or a noble metal. Gaseous hydrogen is commonly used as a reducing agent. The acetylating agent is usually acetic anhydride. The reaction solvent is an inert media such as, for example, acetic acid, water, a water-isopropanol mixture, ethyl acetate, thiophene-free benzol, or a hydrocarbon. Processes of producing acetyl-p-aminophenol which do not require the isolation and purification of p-aminophenol, which is oxidatively unstable, are highly desirable. Unfortunately, the processes of the prior art require the use of undesirable solvents.
In the Celanese Process, as described in U.S. Pat. No. 4,954,652, incorporated herein by reference, N-acetyl-para-aminophenol is prepared by subjecting 4-hydroxyacetophenone oxime to a Beckman rearrangement in the presence of a thionyl chloride catalyst and an alkyl alkanoate as the reaction solvent. The patent also discloses an integrated process wherein 4-hydroxyacetophenone is reacted with a hydroxyl amine salt and a base to obtain the ketoxime of the ketone, e.g. 4-hydroxyacetophenone oxime, extracting the ketoxime product from the reaction with alkanoate ester and subjecting the ketoxime dissolved in ester to a Beckman rearrangement in the presence of a thionyl catalyst. Like the other processes of the prior art, the Celanese Process requires the use of an organic solvent.
Since acetaminophen is the most prescribed analgesic in the world because of its antipyretic activity, a solvent minimized process is desired.
Solvent based chemistry is also needed in the production of nitroaldols. Nitroalcohols are valuable intermediates for the synthesis of pharmacologically active β-amino alcohols: Such alcohols are the key elements present in β-blockers and agonists and are highly effective in the treatment of cardiovascular disease, asthma, and glaucoma. Nitroalkenes derived from nitroalcohols possess significant biological activities such as insecticidal, fungicidal, bactericidal, rodent-repellant and antitumor agents and are also utilized for the preparation of a variety of important organic compounds including prostaglandins, pyrroles, porphyrins, as set forth below: 
Traditional synthesis of nitroalcohols involving the base catalyzed condensation of aldehydes or silyl nitronates with the corresponding nitroalkanes are low yielding (50-60%), prohibitively slow (4-7 days) and waste producing. A synthesis involving potassium fluoride promoted aldol-like condensation of an aldehyde with 1-nitroalkane in polar protic solvent (e.g. isopropanol) has further been reported. Complicated unit operations, poor conversion and disposal of solvents, CaF2, celite, waste layers and salts from aqueous acid base extractions make this process environmentally unattractive. Further, an alternate synthesis of nitro alcohol involving addition of N2O4 or acylnitrate to an olefin has been proposed: Unfortunately, such synthesis is impractical and costly.
Alternative synthesis have further been sought for the production of oxazinones and thiazoles, including benzothiazoles. Such fused heterocycles are of considerable interest owing to their biological activity. For example, benzooxazin-4-ones (acylanthranils) act as chrymotripsin inactivators, inhibitors of human leukocyte elastase, serin protease and 2-aryl derivatives and have the ability to lower the concentration of plasma cholesterol and triglyceride. Moreover, 2-substituted-4H-3,1-bezoxazin-4-ones have been reported to be used as precursors for the preparation of pharmaceutically active compounds such as antimicrobial agents. See, for instance, Organic Letters, 1, 10, 1619-22, 1999.
Further, heterocycles containing the thiazole moiety are present in many natural products such as bleomycin, epothilone A, lyngbyabellin A and dolastatin 10. Benzothiazole derivatives are of particular interest in light of their antimicrobial properties and applications in industry as antioxidants and vulcanization accelerators.
Therefore, a need exists for the development of a synthesis of organic compounds, including nitroalcohols, acetaminophen, indoles, thiazoles and oxazinones, using an efficient catalytic method in a solvent minimized environment.